Is ASPA p.Cys218Ter (c.654C>A) pathogenic?

ASPA p.Cys218Ter (c.654C>A) is classified Pathogenic in ASPA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-26). Very rare (popmax 0.0022%, sas); Associated with Canavan Disease, Familial Form.

What condition is associated with ASPA p.Cys218Ter (c.654C>A)?

ASPA p.Cys218Ter (c.654C>A) is associated with Canavan Disease, Familial Form, Canavan disease (ClinVar).

How common is ASPA p.Cys218Ter (c.654C>A) in the general population?

ASPA p.Cys218Ter (c.654C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

ASPA p.Cys218Ter

c.654C>A · rs104894549 · VCV2608

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Canavan Disease, Familial Form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.6, phastCons 0.98
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,040 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00031% 5/1,611,054 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,520
Remaining individualsnot grpmax-eligible	0.0016%	62,386
European (non-Finnish)	0.00017%	588,682

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ASPA
Protein: p.Cys218Ter
Coding: c.654C>A
MANE Select: NM_000049
dbSNP: rs104894549
Type: single nucleotide variant
Location: chr17:3494369 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB
Residue 218: a β-strand

Full ASPA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Canavan Disease, Familial Form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Canavan disease

Similar variants

ASPA p.Cys218= Likely benign ★★ same residue
ASPA c.236+2T>C Likely pathogenic ★★ same condition
ASPA c.237-1G>T Likely pathogenic ★★ same condition
ASPA c.237-2A>T Pathogenic/Likely pathogenic ★★ same condition
ASPA c.527-1G>A Likely pathogenic ★★ same condition
ASPA c.527-2A>C Likely pathogenic ★★ same condition
ASPA c.527-2A>G Likely pathogenic ★★ same condition
ASPA c.634+1G>T Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aspa-p-cys218ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown